The field of the invention is alleviation of vasoconstriction and vasospasm.
Vasoconstriction and vasospasm are important causes of ischemic damage in a wide variety of human maladies, including, for example, ischemic heart diseases such as myocardial infarction, angina pectoralis, and atherosclerotic injury, stroke, cerebral vasoconstriction, and cramps and ischemic muscle injury associated with muscle spasm.
Chronic delayed cerebral vasoconstriction (CDCV) following aneurysmal subarachnoid hemorrhage (SAH) is a serious and often fatal condition in humans. Considerable clinical and laboratory evidence has accumulated to indicate that endothelin-1 (ET-1) is involved in development of CDCV following SAH (Suzuki et al., 1990, Annals of Medicine 22:233-236; Suzuki et al., 1992, J. Neurosurgery 77:96-100; Fuwa et al., 1993, Neurologia Medico-Chirurgica 33:739-743; Kasuya et al., 1993, J. Neurosurgery 79:892-98; Ohlstein et al., 1992, J. Neurosurgery 77:274-278). A similar body of evidence exists for role of ET-1 in the failure of intrinsic vasodilatory mechanisms in the cerebral blood vessel wall as a result of SAH (Hongo et al., 1988, J. Neurosurgery 69:247-253; Snyder et al., 1992, Scientific American 266:68-77; Toda et al., 1993, Stroke 24:1584-1588).
The action of nitric oxide (NO) is implicated in intrinsic local vasodilation mechanisms. NO is the smallest biologically active molecule known and is the mediator of an extraordinary range of physiological processes (Nathan, 1994, Cell 78:915-918; Thomas, 1997, Neurosurg. Focus 3:Article 3). NO is also a known physiologic antagonist of endothelin-1, which is the most potent known mammalian vasoconstrictor, having at least ten times the vasoconstrictor potency of angiotensin II, which has been implicated in CDCV by many investigations (Yanagisawa et al., 1988, Nature 332:411-415; Kasuya et al., 1993, J. Neurosurg. 79:892-898; Kobayashi et al., 1991, Neurosurgery 28:5:673-679). The biological half life of NO is extremely short (Morris et al., 1994, Am. J. Physiol. 266:E829-E839; Nathan, 1994, Cell 78: 915-918, 1994). NO accounts entirely for the biological effects of endothelium-derived relaxing factor (EDRF) and is an extremely potent vasodilator that works through the action of cGMP-dependent protein kinases to effect vasodilation (Henry et al., 1993, FASEB J. 7:1124-1134; Nathan, 1992, FASEB J. 6:3051-3064; Palmer et al., 1987, Nature 327:524-526; Snyder et al., 1992, Scientific American 266:68-77).
As a free radical gas, NO is difficult to measure directly, but two pieces of evidence support its insufficiency or dysfunction during SAH-induced cerebral vasospasm. First, cGMP is depleted in the vessel wall following SAH and second, oxyhemoglobin, released by erythrocyte lysis in the SAH clot, binds NO avidly (Gibson et al., 1957, Am. J. Physiol. 136:507-526; Kim et al., 1992, Circulation Research 70:248-56; Martin et al., 1985, J. Pharmacol. Exp. Ther. 232:708-716).
It is likely that the phenomenon of CDCV simultaneously involves the increased activity of ET-1 and the decreased activity of NO. Validation of such a hypothesis requires that attenuation or reversal of CDCV by either interfering with the action of ET-1 or by somehow making NO more available to the blood vessel wall is demonstrated. This has been attempted by several groups of investigators using different methods with varying degrees of success. The former strategy has enjoyed more popularity in the recent literature and the use of endothelin receptor antagonists to attenuate CDCV has provided promising initial results (Foley et al., 1994, Neurosurgery 34:108-113; Itoh et al., 1994, J. Neurosurgery 81:759-764).
One important limitation of the use of NO donors in vivo has been their tendency to induce severe systemic hypotension (Heros et al., 1976, Surgical Neurology 5:354-362; Raynor et al., 1963, J. Neurosurgery 20:94-96). A reliably effective treatment for CDCV that follows aneurysmal SAH remains elusive. The mainstay of treatment for this complication, now the most important cause of mortality and neurological morbidity following aneurysmal SAH, is hypertensive/hypervolemic/hemodilution (HHH) therapy (Solomon et al., 1998, Neurosurgery 23:699-704). Because severe cases of CDCV are refractory to HHH therapy, and because some patients do not tolerate HHH therapy for medical reasons, an alternative treatment for CDCV is needed. Effective treatments for vasoconstriction and vasospasm in cerebral and other tissues are needed, as are prophylactic treatments for preventing vasoconstriction and vasospasm.
The present invention satisfies these needs.
The invention relates to a method of alleviating vasoconstriction in a mammal. The method comprises adventitially administering a nitric oxide donor compound to a constricted blood vessel in the mammal. Constriction of the blood vessel is thereby alleviated. In one embodiment of this method, the animal is a human, and the blood vessel is selected from the group consisting of a cerebral blood vessel, the right anterior cerebral artery, the right middle cerebral artery, the right posterior communicating artery, the left anterior cerebral artery, the left middle cerebral artery, the left posterior communicating artery, a cardiac blood vessel, the right coronary artery, the left coronary artery, and a blood vessel situated within a spastic muscle tissue. Preferably, the blood vessel is a cerebral blood vessel and the compound is adventitially administered to the blood vessel by delivering the compound to the cerebrospinal fluid of the mammal. One way of achieving this is to deliver the compound to the cerebrospinal fluid of the mammal by withdrawing an aliquot of the cerebrospinal fluid from the subarachnoid space of the mammal, to combine the compound with the aliquot of cerebrospinal fluid, and then to return the cerebrospinal fluid to the subarachnoid space of the mammal. Another way to achieve this is to deliver the compound to the cerebrospinal fluid of the mammal by withdrawing an aliquot of the cerebrospinal fluid from the subarachnoid space of the mammal, to combine a pharmaceutical composition comprising the compound with the aliquot of cerebrospinal fluid, and then to return the cerebrospinal fluid to the subarachnoid space of the mammal.
In another embodiment of this method, the blood vessel is a cardiac blood vessel, and the compound is adventitially administered by providing the compound to the pericardial cavity of the mammal.
The mammal of this method may, for example, be selected from the group consisting of a mammal experiencing chronic delayed cerebral vasoconstriction, a mammal which has experienced a subarachnoid hemorrhage, a mammal which has experienced an aneurysmal subarachnoid hemorrhage, a mammal experiencing an early embolic stroke, a mammal which has experienced a stroke, a mammal experiencing cardiac ischemia, a mammal which has experienced a myocardial infarction, a mammal afflicted with angina pectoralis. Preferably, the mammal is a human.
In one embodiment of this method, the compound is administered in the form of a sustained-release formulation of the compound. The compound may, for example, be selected from the group consisting of nitroglycerine, arginine, and a nitroprusside salt. Preferably, the compound is sodium nitroprusside (SNP). The dosage of SNP for an adult human in a one-day period is in the range from about 10 milligrams to 88 milligrams, more preferably from about 10 milligrams to 30 milligrams.
In another embodiment of this method, the compound is administered in the form of a pharmaceutical composition comprising the compound and a scavenger compound selected from the group consisting of a cyanide scavenger, a cyanate scavenger, hydroxycobalamin, and thiosulfate.
Preferably, the amount of the NO donor compound administered to the blood vessel is an amount that is sufficient to alleviate constriction of the blood vessel, but that is insufficient to induce systemic hypotension or cerebral hypertension in the mammal.
Another embodiment of this method comprises administering to the mammal a compound selected from the group consisting of an anti-inflammatory agent, a antibiotic, an oxyhemoglobin-reducing compound, a thrombolytic agent, and anti-emetic compound to said mammal.
The invention also relates to a method of preventing vasoconstriction in a mammal. This method comprises adventitially administering a nitric oxide donor compound to a blood vessel in the mammal, whereby constriction of the blood vessel is prevented. Preferably, the nitric oxide donor compound is sodium nitroprusside. Also preferably, the mammal is a human, and the amount of sodium nitroprusside administered to the human in a one-day period is not more than 24 milligrams, more preferably in the range from 4 to 24 milligrams. Also preferably, the nitric oxide donor compound is administered in the form of a pharmaceutical composition comprising a sustained-release formulation of the compound.
The invention further relates to a method of dilating a constricted or spastic blood vessel in a mammal. This method comprises adventitially administering a nitric oxide donor compound to the blood vessel, whereby the blood vessel dilates.
The invention further relates to a method of alleviating ischemia in a tissue of an animal. This method comprises administering a nitric oxide donor compound to the tissue, whereby the compound is administered to a blood vessel in the tissue, thereby alleviating constriction or spasm of the blood vessel and alleviating ischemia in the tissue.
The invention still further relates to a method of preventing ischemia in a tissue of an animal. This method comprises administering a nitric oxide donor compound to the tissue, whereby the compound is administered to a blood vessel in the tissue, thereby preventing constriction of the vessel and preventing ischemia in the tissue.
The invention also relates to a vasodilating composition for adventitial administration to a constricted or spastic blood vessel of a mammal, the composition comprising a nitric oxide donor compound and a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier is selected from the group consisting of the cerebrospinal fluid of the mammal and a synthetic cerebrospinal fluid.
In addition, the invention further relates to a device for delivering to a mammal a pharmacological agent having a short half-life in solution. This device comprises:
a first hollow body having a flow orifice, a first fluid access port, and a first pressure orifice, each in fluid communication with the interior of the first hollow body;
a second hollow body for containing the pharmacological agent, the second body having a second fluid access port in fluid communication with the interior of the second hollow body and in fluid communication with the first fluid access port, and an outlet port in fluid communication with the interior of the second hollow body; and
a first pressure modulator connected to the first pressure orifice.
In one embodiment, this device further comprises a valve having an inlet orifice coupled to the outlet port and an outlet orifice, wherein the valve permits fluid flow in the direction from the inlet orifice to the outlet orifice. Preferably, the outlet orifice is in fluid communication with the interior of the first hollow body
In another embodiment of this device, the second hollow body contains the pharmacological agent in the interior thereof. Preferably, the pharmacological agent is a nitric oxide donor compound, even more preferably a single human intrathecal delivery amount of the nitric oxide donor compound.
In yet another embodiment of this device, the second hollow body further comprises at least one compartment containing the pharmacological agent, wherein the interior of the compartment is separated from the interior of the second hollow body by a breachable barrier. Preferably, the breachable barrier comprises a polymeric film or a foil, such as a film having at least one score or a film having at least one perforation. In one version, this device further comprises a compartmental plunger slidably disposed within the compartment for breaching the barrier, wherein when the compartmental plunger is actuated, the barrier is breached, whereby the composition is brought into fluid communication with the interior of the second hollow body.
In another embodiment of device of the invention, the pressure modulator comprises a first plunger snugly slidably disposed within the interior of the first hollow body, the first plunger being positionable within the first hollow body between an advanced position and a retracted position, wherein the flow orifice is not in fluid communication with the fluid access port when the first plunger is positioned in the advanced position, and wherein the flow orifice is in fluid communication with the fluid access port when the first plunger is positioned in the retracted position. Preferably, the device of this embodiment further comprises a second plunger snugly slidably disposed within the second hollow body, whereby when the second plunger is urged in the direction of the outlet port, the contents of the second hollow body are discharged through the outlet port. Thus, according to one embodiment, the first hollow body is a first syringe, wherein the second hollow body is a second syringe, and the interiors of the first and second syringes are connected to the interior of a ventriculostium by means of a three-way valve, wherein the three-way valve selectably connects any two of the interior of the first syringe, the interior of the second syringe, and the interior of the ventriculostium.
In another embodiment of the device of the invention, the second hollow body is disposed within the interior of the first hollow body; the first hollow body and second hollow body are substantially longitudinally coaxial; the outlet orifice is disposed in close proximity to the flow orifice; and the flow orifice is adaptable to a cerebrospinal fluid drainage system.
The invention also relates to a subdural catheter comprising a flexible, generally tubular body having an outer surface, a proximal end, a distal end, a lumen extending within the body from the proximal end, at least one hole extending through the body from the outer surface to the lumen, and a hub at the proximal end for attaching the catheter to a fluid handling device. Preferably, the body has a flattened cylindrical shape. Also preferably, the body is at least partially radio opaque. In one embodiment of the subdural catheter, the width of the lumen at the distal end of the body is greater than the width of the lumen at the proximal end of the body.
The invention further relates to a subdural insertional guide. The guide comprises a substantially rigid body having a long axis, a proximal end, a distal end, an outer surface, and a lumen extending within the body from the proximal end to the outer surface, wherein the lumen extends generally parallel to the long axis at the proximal end of the body and generally perpendicular to the long axis at the outer surface, wherein when the distal end of the body is inserted into a trephination in the skull of a mammal, the lumen is in fluid communication with a subdural space in the mammal. In one embodiment, the subdural insertional guide further comprising an inflatable balloon at the distal end of the body.
The invention still further relates to a kit for dilating a blood vessel in a mammal. This kit comprises a nitric oxide donor compound and an instructional material which describes adventitially administering the compound to a blood vessel of the mammal.
The invention yet further relates to a kit for dilating a constricted or spastic blood vessel in a mammal. This kit comprises at least one syringe containing a nitric oxide donor compound in a substantially anhydrous form and a three-way valve for connecting the syringe with a second syringe and with a liquid conduit in fluid communication with the adventitial surface of a the blood vessel.
The invention also relates to a kit for intrathecal administration of a nitric oxide donor compound to a mammal. This kit comprises:
a) a device for administering the compound, the device comprising:
a first hollow body having a flow orifice, a first fluid access port, and a first pressure orifice, each in fluid communication with the interior of the first hollow body;
a second hollow body for containing the compound, the second body having a second fluid access port in fluid communication with the interior of the second hollow body and in fluid communication with the first fluid access port, and an outlet port in fluid communication with the interior of the second hollow body; and
a valve having an inlet orifice coupled to the outlet port and an outlet orifice, wherein the valve permits fluid flow in the direction from the inlet orifice to the outlet orifice; and
b) an instructional material which describes use of the device to intrathecally administer the compound to the mammal.
The invention further relates to a subdural catheterization kit comprising a subdural catheter comprising a flexible, generally tubular catheter body having an outer surface, a proximal end, a distal end, a lumen extending within the catheter body from the proximal end, at least one hole extending through the catheter body from the outer surface to the lumen, and a hub at the proximal end for attaching the catheter to a fluid handling device; and,
a subdural insertional guide, the guide comprising a substantially rigid guide body having a long axis, a proximal end, a distal end, an outer surface, and a lumen extending within the guide body from the proximal end to the outer surface, wherein the lumen extends generally parallel to the long axis at the proximal end of the guide body and generally perpendicular to the long axis at the outer surface, wherein when the distal end of the guide body is inserted into a trephination in the skull of a mammal, the lumen is in fluid communication with a subdural space in the mammal.